PROJECT 2: SUMMARY/ABSTRACT Kejal Kantarci, M.D. The social and economic implications of dementia will be greatest in women because of their longer life expectancy and resulting elevated risk for dementia compared to men. This risk of dementia in women may be, in part, modulated by ovarian hormones and modified by the apolipoprotein E (APOE) ?4 genotype. Women who undergo bilateral salpingo-oophorectomy (BSO) before the onset of menopause have an accelerated accumulation of multimorbidity, with an increased risk of aging-related neurological diseases including dementia. How bilateral salpingo-oophorectomy (BSO) influences the risk of dementia remains unknown, but needs to be addressed, because it is estimated that one in eight U.S. women have their ovaries removed before reaching natural menopause. The most common pathologies that contribute to cognitive impairment and dementia in women are Alzheimer's disease (AD) and cerebrovascular disease (CVD). Determining the effects of BSO before menopause on the risk of dementia would require decades of follow-up; alternatively, non-invasive imaging biomarkers can potentially assess the effects of an abrupt loss of ovarian hormones on the risk of AD and CVD pathologies in a shorter time frame. Our goal in Project 2 is to understand the effects of abrupt disruption of ovarian hormones on AD and CVD pathophysiology in women who underwent BSO before reaching menopause through imaging biomarkers. We will enroll 100 women with BSO and 100 referent women that will be drawn from a well-characterized and established population-based cohort. We hypothesize that imaging biomarkers of AD and CVD pathophysiology will be more abnormal in women who underwent BSO before reaching menopause, compared to an age-matched referent cohort of women who did not undergo premenopausal BSO, and that this difference is modulated by APOE ?4. We will further investigate the relationship of imaging biomarkers with cognitive outcomes as measured in Project 1.The results of the proposed research will address this problem by applying state-of-the art imaging and cognitive testing in a population-based cohort of women. Evaluation of this sample of women, whose midlife history of premenopausal BSO is well-characterized, provides a unique opportunity to clarify the long-term effects of abrupt ovarian hormonal disruption on the risk of cognitive decline and dementia through imaging biomarkers of early pathology. For women considering BSO for cancer prophylaxis, the findings will provide critical insights, guiding their health care decisions.